Than N, Shah N, White J, Lee J A, Orchard C H
Department of Physiology, University of Leeds, United Kingdom.
Cardiovasc Res. 1994 Aug;28(8):1209-17. doi: 10.1093/cvr/28.8.1209.
The aim was to study the effects of acidosis and hypoxia on the response of cardiac muscle to inotropic agents which (a) act predominantly by increasing intracellular [Ca2+] (raising extracellular [Ca2+], noradrenaline, isoprenaline) and (b) act partly (phenylephrine) or predominantly (EMD 57033) by increasing myofilament calcium sensitivity.
The experiments were performed on isometrically contracting, isolated ferret papillary muscles (n = 45). For each intervention dose-response curves were performed in control solution (pH 7.35), in hypercapnic acidosis (pH 6.85), and in hypoxia (produced by replacing O2 with N2 in the superfusing solution). In some experiments, the photoprotein aequorin was microinjected into superficial cells of the preparation in order to measure intracellular [Ca2+] as well as force.
The results were broadly similar for both classes of inotropic agent. Acidosis caused a shift of the pCa-tension curve to the right (desensitisation of the myofilaments to calcium), but had no significant effect on maximum force. A sufficient inotropic stimulus supplied by either class of inotropic agent could completely reverse the negative inotropic effects of acidosis. The main difference between the two inotropic mechanisms was that the enhanced force produced by calcium sensitisers was associated with a reduction in calcium transient amplitude, while the other inotropes increased the amplitude. The main effect of hypoxia was to decrease maximum force. All the inotropes tested were relatively ineffective in reversing the force depression due to hypoxia.
The negative inotropic effects of acidosis can be reversed by a sufficiently large inotropic stimulus. Since calcium transient amplitude is already increased in acidosis, the results suggest that calcium sensitisers are likely to be less arrhythmogenic in this situation. The relative ineffectiveness of the inotropes in hypoxia indicates that the main mechanisms causing reduced force in this situation lie downstream of the mechanisms of action of the inotropic agents tested.
本研究旨在探讨酸中毒和缺氧对心肌收缩性药物反应的影响，这些药物包括：（a）主要通过增加细胞内[Ca2+]（提高细胞外[Ca2+]、去甲肾上腺素、异丙肾上腺素）起作用的药物，以及（b）部分（去氧肾上腺素）或主要（EMD 57033）通过增加肌丝钙敏感性起作用的药物。
实验在等长收缩的离体雪貂乳头肌上进行（n = 45）。对于每种干预措施，在对照溶液（pH 7.35）、高碳酸血症性酸中毒（pH 6.85）和缺氧（通过用N2替换灌注溶液中的O2产生）条件下进行剂量反应曲线实验。在一些实验中，将光蛋白水母发光蛋白微量注射到标本的表层细胞中，以测量细胞内[Ca2+]和力量。
两类收缩性药物的结果大致相似。酸中毒导致pCa-张力曲线右移（肌丝对钙脱敏），但对最大力量无显著影响。任何一类收缩性药物提供的足够的收缩性刺激都能完全逆转酸中毒的负性肌力作用。两种收缩性机制的主要区别在于，钙敏化剂产生的增强力量与钙瞬变幅度的降低有关，而其他正性肌力药物则增加了幅度。缺氧的主要作用是降低最大力量。所有测试的正性肌力药物在逆转缺氧引起的力量降低方面相对无效。
足够大的收缩性刺激可逆转酸中毒的负性肌力作用。由于酸中毒时钙瞬变幅度已经增加，结果表明钙敏化剂在这种情况下可能致心律失常的可能性较小。正性肌力药物在缺氧时相对无效，这表明在这种情况下导致力量降低的主要机制位于所测试的正性肌力药物作用机制的下游。
